1. Field of the Invention
The present invention relates to novel dinitrogen substitued derivatives of epipodophyllotoxin glucosides, to their therapeutic anti-tumor use, and to pharmaceutical dosage forms containing these new agents.
2. Description of the Related Art
Etoposide (VP-16, Ia) and teniposide (VM-26, Ib) are clinically useful anticancer agents derived from the naturally occurring lignan, podophyllotoxin (II). The numbering system used for nomenclature purpose is shown in Formula II. Etoposide and teniposide are epipodophyllotoxin ##STR1## derivatives; epipodophyllotoxin being the epimer of podophyllotoxin at the 4-position. Etoposide and teniposide are active in the treatment of a variety of cancers including small cell lung cancer, non-lymphocytic leukemia, and non-seminomatous testicular cancer (AMA Drug Evaluation, 5th Edition, American Medical Association, 1983, Chicago, Ill., p. 1554-5).
Etoposide and teniposide, and methods for producing them, are disclosed in U.S. Pat. No. 3,524,844 to Keller-Juslen et al. Etoposide 3',4'-quinone (IIIa) has been generated from electrochemical oxidation of etoposide (Holthuis J. J. M., et al, J. Electroanal. Chem. Interfacial Electrochem., 1985, 184(2): 317-29). The preparation of the quinone III by chemical oxidation is disclosed in U.S. Pat. No. 4,609,644 to Josef Nemec. Epipodophyllotoxin 3',4'-quinone derivatives III wherein A and Y have the definition given hereinbelow for Formula IV, serve as the starting material for our preparation of the nitrogen containing epipodophyllotoxin derivatives of the present invention. ##STR2##
Ayres and Lim in Cancer Chemother Pharmacol, 1982, 7: 99-101 discloses the podophyllotoxin having the formula ##STR3##